I. Immune Complex Mediated Disease
The formation of immune complexes is the typical consequence of the interaction of antigens with specific antibodies. The inflammatory response that ensues when such complexes accumulate in a limited area is an important element of normal host defenses, leading to immune complex clearance and antigen destruction by phagocytic cells. In contrast, immune complex diseases are reflections of excess complex formation or retarded clearance, usually under conditions of exceptional antigen challenge or immunologic dysregulation. Under such circumstances, immune complexes are deposited or formed at specific tissue sites and resulting inflammatory responses lead to disease states due to localized or systemic tissue damage. The kidney, and more specifically the kidney structure known as the glomerulus, is a particularly important site of immune complex deposition resulting in the development of serious disease conditions.
II. Glomerulonephritis
The glomerulus is a key structural and functional element of the kidney. Each glomerulus is found as part of a larger structure that serves as the main functional unit of the kidney and is called a nephron. About a million nephrons are found in each kidney. Each glomerulus is a network of up to fifty parallel capillaries encased in a structure known as Bowman's capsule. The area inside Bowman's capsule that is not taken up by the glomerular capillaries is known as Bowman's space. The glomerulus functions as a filter, separating water and certain solutes from the proteins and cells of the blood into Bowman's space for further processing in the convoluted tubules, loop of Henle, and collecting duct of the nephron.
Glomerulonephritis (GN) is a disease of the kidney characterized by inflammation and resulting enlargement of the glomeruli that is typically due to immune complex formation. The accumulation of immune complexes in the glomeruli results in inflammatory responses, involving inter alia hypercellularity, that can cause total or partial blockage of the glomerulus through, among other factors, narrowing of capillary lumens. One result of this process is the inhibition of the normal filtration function of the glomerulus. Blockage may occur in large numbers of glomeruli, directly compromising kidney function and often causing the abnormal deposition of proteins in the walls of the capillaries making up the glomerulus. Such deposition can, in turn, cause damage to glomerular basement membranes. Those glomeruli that are not blocked develop increased permeability, allowing large amounts of protein to pass into the urine, a condition referred to as proteinuria.
In many cases of severe GN, pathological structures called crescents are formed within the Bowman's space, further impeding glomerular filtration. These structures can only be seen by microscopic examination of tissue samples obtained by biopsy or necropsy, and are thus not always observed in those patients in which they occur. Crescents are a manifestation of hypercellularity and are thought to arise from the extensive abnormal proliferation of parietal epithelial cells, the cells that form the inner lining of the Bowman's capsule. Clinical research has shown that there is a rough correlation between the percentage of glomeruli with crescents and the clinical severity of the disease, and thus the patient's prognosis. When present in large numbers, crescents are a poor prognostic sign.
Symptoms of GN include: proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen--BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria.
In 1990, over 210,000 patients in the United States required hemodialysis or transplantation for chronic renal failure at an annual cost in excess of 7 billion dollars, according to the United States Renal Data System (USRDS). The USRDS compiles data on kidney disease in the United States in conjunction with the National Institute of Diabetes and Digestive and Kidney Diseases, Division of Kidney, Urologic, and Hematologic Diseases, of the National Institutes of Health (NIDDKD). The USRDS estimates that the costs of treatment for renal failure are now increasing by 20 percent annually.
GN is the third leading cause of death in end-stage renal disease patients, exceeded only by diabetes and hypertension. As a result, there is a clear and long felt need in the medical community for effective treatments for this condition. Research aimed at the development of new treatments for GN is ongoing worldwide. In the United States, the NIDDKD, the National Kidney Foundation, and several other public and private organizations sponsor research in this area. The National Kidney Foundation alone supplies over two million dollars annually to fund the efforts of kidney researchers.
III. Current Treatments for GN
Corticosteroid administration, typically as high doses of "pulse" intravenous methylprednisolone or oral prednisone therapy, is currently considered the most effective pharmacologic agent available for the treatment of GN. Such steroid therapy is often administered in combination with cytotoxic general immunosuppressive agents such as azathioprine or cyclophosphamide. The overall immune suppression and resulting increased susceptibility to infection, along with other debilitating side effects associated with both steroid and cytotoxic drug administration, limit the effective use of these drugs.
Aspirin-like non-steroidal anti-inflammatory drugs (NSAIDs) have also been used to reduce the glomerular inflammation and enlargement of GN. These drugs are not routinely used for this purpose, however, probably because of their relatively weak anti-inflammatory effects and propensity to cause gastrointestinal and other side effects in many patients.
The administration of anticoagulants such as heparin or warfarin sodium, and antithrombotic agents such as cyproheptadine, dipyridamole, or sulfinpyrazone, has been used on the basis of evidence suggesting the involvement of the coagulation process in the genesis of glomerular crescents. However, objective evidence of benefit from such therapies in animals afflicted with experimentally induced crescentic GN has been inconsistent. Also, anticoagulants are dangerous drugs, as they can potentiate life-threatening bleeding episodes. They are especially hazardous in this regard in patients with advanced renal failure.
In addition to pharmacologic approaches, intensive plasma exchange (plasmapheresis) of 2 to 4 liters of plasma daily (or in some cases three times a week) can dramatically reduce high levels of circulating immune complexes when acute intervention in the inflammatory process is needed. Such treatment is expensive and requires that the patient be connected to the plasmapheresis machine for many hours each week. In addition, all procedures in which blood is removed from and returned to a patient are associated with an increased risk of infection. Nonetheless, plasma exchange is currently considered the most effective non-pharmacological treatment for removal of circulating immune complexes which can cause GN.
Circulating immune complex levels can also be decreased by eliminating or reducing the source of the antigen or antigens contained in the complexes by, for example, effective therapy of an underlying infection or change in an antibiotic. However, while such therapy is almost always a treatment of choice, great care must be taken since reduction of the antigen load alters the molar ratio of antigen to antibody involved in forming immune complexes and thus a dangerous temporary exacerbation of the inflammatory process may occur (see discussion below in Background Physiology & Pathology).